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Molecular Pharmacology Fast Forward
First published on July 8, 2008; DOI: 10.1124/mol.108.048652

0026-895X/08/7404-925-932$20.00
Mol Pharmacol 74:925-932, 2008

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Accelerated Communication

Targeting Ceramide Metabolism with a Potent and Specific Ceramide Kinase InhibitorFormula

Christine Graf, Martin Klumpp, Michael Habig, Philipp Rovina, Andreas Billich, Thomas Baumruker, Berndt Oberhauser, and Frédéric Bornancin

Novartis Institutes for BioMedical Research, Vienna, Austria (C.G., P.R., A.B., T.B., B.O., F.B.), and Basel, Switzerland (M.K., M.H.)

Ceramide kinase (CerK) produces the bioactive lipid ceramide-1-phosphate (C1P) and appears as a key enzyme for controlling ceramide levels. In this study, we discovered and characterized adamantane-1-carboxylic acid (2-benzoylamino-benzothiazol-6-yl)amide (NVP-231), a potent, specific, and reversible CerK inhibitor that competitively inhibits binding of ceramide to CerK. NVP-231 is active in the low nanomolar range on purified as well as cellular CerK and abrogates phosphorylation of ceramide, resulting in decreased endogenous C1P levels. When combined with another ceramide metabolizing inhibitor, such as tamoxifen, NVP-231 synergistically increased ceramide levels and reduced cell growth. Therefore, NVP-231 represents a novel and promising compound for controlling ceramide metabolism that may provide insight into CerK physiological function.

Received May 6, 2008; accepted July 1, 2008

Address correspondence to: Frédéric Bornancin, Current affiliation: Novartis Institutes for BioMedical Research, Forum 1, CH-4056 Basel, Switzerland. E-mail: frederic.bornancin{at}novartis.com






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